In simplest terms, osteoarthritis can be understood as the wearing away of articular cartilage, a tissue with a limited ability to repair itself. Findings from recent studies suggest that progressive degradation in cartilage after injury is closely related to the elevation and activation of specific enzymes, called metalloproteinases. In addition to possible treatments, joint load such as during physical therapy or exercise can affect matrix biosynthesis and the degradative events depending on the courses of loading. A better understanding of the mechanobiology of injured cartilage and the effects of cyclic loads on tissue degradation is an important step for optimizing the treatments for cartilage degeneration. In this application, we hypothesize that cyclic load modulates tissue degeneration following injury and affects the efficacy of metalloproteinase inhibitors. Taking advantage of an in vitro model system developed recently in our laboratory, we propose to study how daily load (immobilization vs. low and moderate cyclic compression) affects specific degradative events and the treatments of cartilage following defined subfracture injury. Our specific aims are: 1) to determine the effects of daily load on matrix biosynthesis, cytokine level, matrix degradation, cell apoptosis, and biomechanical properties; and 2) to determine the efficacy of matrix metalloproteinase inhibitors (MMPI) on preventing matrix degeneration in the presence of daily load. The outcomes will be tested at the molecular, cellular and structural levels by determining the level of cytokines, elevation/activation of metalloproteinases, matrix (proteoglycan and collagen) loss and degradation, matrix biosynthesis, collagen network integrity (tissue swelling), and tissue biomechanical properties in the cartilage for up to 7 days after injury. The significance is two fold, first to determine the mechanobiology of injured cartilage and second to understand how mechanical load influences therapeutic treatments such as the use of MMPIs. We believe the results of this study will significantly impact the ways to treat cartilage degeneration in traumatic osteoarthritis and other types of arthritis. [unreadable] [unreadable] [unreadable]